Abstract
Diabetic nephropathy (DN) is one of the primary complications of diabetes. Fisetin is a flavonoid polyphenol that is present in several vegetables and fruits. The present study investigated the mechanisms of fisetin in DN-induced podocyte injury both in vitro and in vivo. The results revealed that fisetin ameliorated high glucose (HG)-induced podocyte injury and streptozotocin (STZ)-induced DN in mice. CDKN1B mRNA expression in the glomeruli of patients with DN decreased based on the Nephroseq dataset, and fisetin reversed CDKN1B expression at mRNA and protein levels in a dose-dependent manner in podocytes and mice kidney tissues. Furthermore, fisetin suppressed the phosphorylation of P70S6K, a downstream target of CDKN1B, activated autophagosome formation, and inhibited Nod-like receptor protein 3 (NLRP3) inflammasomes. Interfering CDKN1B reduced the protective effects of fisetin against high glucose-induced podocyte injury. Molecular docking results revealed a potential interaction between fisetin and CDKN1B. In summary, the present study revealed that fisetin alleviated high glucose-induced podocyte injury and STZ-induced DN in mice by restoring autophagy-mediated CDKN1B/P70S6K pathway and inhibiting NLRP3 inflammasome.
Highlights
Diabetic nephropathy (DN) is one of the chronic and severe microvascular complications of diabetes, and a major cause of end-stage renal disease (ESRD)
DN is characterized by injury to podocytes, which could be attributed to high glucose (HG) levels that are known to induce apoptosis in podocytes (Susztak et al, 2006)
The results revealed that the expressions of P-cadherin and ZO-1 decreased considerably at mRNA and protein levels after HG treatment (Figures 1E,F), which suggests that HG accelerated the epithelial-mesenchymal transition (EMT) process in podocytes
Summary
Diabetic nephropathy (DN) is one of the chronic and severe microvascular complications of diabetes, and a major cause of end-stage renal disease (ESRD). Current epidemiological statistics indicate that the global prevalence of diabetes mellitus (DM) is increasing annually, with a considerable increase from 108 million in 1980 to 451 million in 2017, and the number has continued to rise (Carracher et al, 2018). According to the International Diabetes Federation, the number of people with diabetes globally was estimated to be 463 million in 2019, and is expected to increase to 578 million by 2030 and to 700 million by 2045. 30–40% of the people with diabetes develop DN (Saeedi et al, 2019), which predicts a dramatic increase in the number of people with DN. The early detection and management of DN is important in the development of DN (Finkelstein et al, 2012; Sumida and Kovesdy, 2017)
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